The anticipated growth of cell production, virus production, and cell culture-based biomolecule production will require new paradigms for rapid, high-throughput, harvest, purification, concentration and formulation of a variety of cell, viruses, and biomolecules such as proteins and immunoglobulins. Manual methods for producing and purifying these products have their drawbacks. For example, these methods can be labor intensive, time consuming, and are highly inefficient. Large scale manufacturing techniques typically use multiple columns which are manually packed with resin and sterilized prior to each purification run. The manual steps involved in these methods also include a high risk of contamination. Moreover, conventional approaches and tools for these products typically involve numerous manual manipulations that are subject to variations even when conducted by skilled technicians. When used at the scale needed to manufacture hundreds or thousands of different cells, cell lines and patient-specific cell based therapies, for example, the variability, error or contamination rate may become unacceptable for commercial processes.
One type of method for the production of cell-secreted products is to use a bioreactor (e.g., hollow fiber, ceramic matrix, fluidizer bed, etc.) in lieu of the stirred tank. This can bring facilities costs down and increases product concentration. The systems currently available are general purpose in nature and require considerable time from trained operators to setup, load, flush, inoculate, run, harvest, and unload. Each step typically requires manual documentation, which is labor intensive and subject to errors.
Cell culturing devices or cultureware for culturing cells in vitro are known. Hollow fiber perfusion bioreactors (HFBx) were first introduced in 1972 as a model system to study tumors growing at tissue-like densities (R. A. Knazek et al., Science, 1972, 178(56):65-67). This system is a high-density, continuous-perfusion system cell culture system that has been used for the production of secreted proteins such as hybridoma, Chinese hamster ovary cells (CHO), human embryonic kidney (HEK) 293 cells, and other mammalian and insect cells. HFBx have been used in a variety of applications such as bioartificial organs, pharmacokinetics, cell therapy, toxicology, etc. In the mid-1980s, Biovest International (formerly Endotronics, Inc.) developed the first commercial scale HFBx system and ever since, the most common application for this technology has been the large-scale production of mammalian cell-secreted proteins, predominantly monoclonal antibodies.
As disclosed in U.S. Pat. No. 4,804,628, the entirety of which is hereby incorporated by reference, a hollow fiber culture device includes a plurality of hollow fiber membranes. Medium containing oxygen, nutrients, and other chemical stimuli is transported through the lumen of the hollow fiber membranes or capillaries and diffuses through the walls thereof into an extracapillary (EC) space between the membranes and the shell of the cartridge containing the hollow fibers. The cells that are to be maintained collect in the EC space. Metabolic wastes are removed from the bioreactor. The cells or cell products can be harvested from the device.
There is a need for a system and method whereby cells and cell-derived products can be produced on a large-scale in an automated, rapid and sterile manner.